Aikylene dihalide salts of n-dialktl



Patented Aug. 30, 1949 ALKYLENE DIHALI'DE SALTS OF N-DIALKYL- A MIN'OALKY L PHENOTHIAZINES AND THEIR PRODUCTION;

Paul Charpentier, Choisy-Le-Roh France-assignor to Societe des UsinesChimiquesRhone- Poulenc, Paris, France, a: French ,bodycorporate NoDrawing." Application January 26, 1948, Se- Y rial No. 4,462. In FranceFebruary 18, 1947 I'his invention relates to alkylenetdihalide salts ofN-dialkylaminoalkyl-phenothiazines and their production 1 andparticularly to phenothiazine derivatives which are quaternary ammoniumsalts.

In my co-pending application No. 650,747vfiled February 2'7, 1946, Ihave described the production,

of anew class of phenothiazine derivatives which have a markedantidyspnoeic and anti-histaminic activity and therefore an importanttherapeutic value. These compounds conform to the Formula I: r

in which Riand R are hydrogen atoms or alkyl analogous compounds inwhich the amino group V k 'the'valu'es assigned to them above, with adigroups (for example methyL ethyl' and propyll R3 and R4 representalkyl groups (for example methyl, ethyl, propyl, and butyl) and nrepresents an integer greater than 1 (e. g. 2, 3, 4, or 5). The benzenenuclei may carry alkyl or alkoxy substituents and the designation(CR1R2)1L includes not only straight aliphatic chains in which the.

is. linked to the nitrogen atom of the phenothiazine nucleus via abranched aliphatic chain.

In my oo-pending application No. 788,326, filed 1 November 26,1947, Ihave described mono'-quaternary salts ofithe aforesaidcompounds.

According to the present invention new phenothiazine compounds oftherapeutic interest are prepared by reacting a compound of generalFormula I; wherein R1, R2, R3, R4 and n have any of halogeno-alkane.

The products obtained conform to the general 7 Formula II:

B where R1, R2, R3 and R4 and n have any of the successive CRIRZ groupsare identical but also branched aliphatic chains in which successiveCRiRa groups may be diiferent. Thus for example the said designationincludes thebranched chain CH2-C(CH3)2 Examples of such compoundsdescribed in the said application are- N-diethylaminoethyl phenothiazineN-diethylaminopropyl phenothiazine N-dimethylaminoethyl phenothiazine N-(3-dimethylaminopropyl) -phenothiazineN-(2'-dimethylamino-2-methyl-ethy1) phenothiazine thlazine N- (2'-dimethy1amino 1' -methyl-ethy1) -2-meth-'-" oxy-phenothiazine N 7(3'-di methylamino-2 ;2 dimethylpropy1),- phenothiazine f i Further :in"myi co-pending-applicationv 2:.

788,649 fi1edN0vember 28,- 1947, I' have described meanings assigned tothem above, A is a divalent aliphatic radicle and X is a halogen atom.As in the parent compounds the benzene rings may (carry alkyl or alkoxysubstituents.

The following examples serve to illustrate the invention but are not tobe regarded as limiting it in any Way: j

" Example 1 Preparation of the compound of the formula:

1 3 O. N O Br OMuD 1. :54 g. of N-dimethylaminoethyl-phenothiazine aremixed with 1.7 g. of dibromoethane, and the mixture is heated for 6hours on a boiling water bath. The mixture rapidly thickens and thewhole sets; After'coolln'g, the mixture is'powdered andplaced inbenzene, which extracts the Y reagents which have not reacted, Afterrecrystal- 'lisationirom alcohol, the dibromide of the above;

3 4 formula is obtained. Melting point 225226 C. (Maquenne block,instantaneous). Example V Preparation of the compound of the formula:

Preparation of the compound of the formula: 5 Oj Oi Ij Example II Br CHHz-CHz-fiT-C-CHz-Clih-CHz-N-CHrCH9 01 N 10 Cfia \CH3 Ca CH1CH2CHzNCH2CHz-CH:NCH2- Hz 4 C 3 By proceeding as in Example I but using5.4

g. of N-dimethylaminoethyl-phenothiazine and 2 g. of1:4-dibromo-pentane, there is obtained the dibromide of the aboveformula. Melting point 221 C. (Maquenne block, instantaneous).

By proceeding as in Example I but using 5.4 g. ofN-dimethylaminoethyl-phenothiazine and 1 g. of 1:3-dichloro-propane,there is obtained, after recrystallisation from alcohol, the dichlorideof Example the above formula. Melting point 198-200 C. (Maquenne block,instantaneous). 2 Preparation of the compound of the formula:

Example III S s Preparation of the compound of the formula:

s s N /Br Br N o z-CHz-N;\OHg-CHz-CHz-CHz-CH2-CH; om cm C CH3 CH3 CH3 rr T 3 0 By proceeding as in Example I but using 5.4 on: CH1 C CH; g. ofN-dimethylaminoethyl-phenothiazine and 2.2 g. of lzfi-dibromohexane,there is obtained By proceeding as in Example I but using 5,4 thedibromide of the above formula which melts g. ofN-dimethylaminoethyl-phenothiazine and at 185-186 C. (Maquenne block,instantaneous). 1.9 g. of 1:4-dibromo-butane, there is obtained thedibromide of the above formula. Melting Example VII point 218 C.(Maquenne block, instantaneous). Preparation of the compound of theformula:

| HgCHPN CHr-CHr-CHr-CHz-CHr-CHz-CHr-N-CHz-CH: Ca CH: CE; CH;

Example IV Preparation of the compound of the formula: By proceeding asin Example I but using g. of N-dimethylaminoethyl-phenothiazine and 2.3g. of 1:7-dibromoheptane, there is obtained the dibromide of the aboveformula. Melting B N point about 150 C. (Maquenne block, instan- N Brtaneous).

CH N-CH CH CH CH 011 N-CH CH CH2- 2- z- 2- r 2- Z 2- 2 Example VIII CH3CH3 C 3 CH3 7 By proceeding as in Example I but using 5.4 Preparation ofthe compound of the formula:

O D 0 1) r r r CHzCH7N CHrCHPCHFCHPCH7NTCHPCH2 C2 a Ca s C2115, C2115 g.of N-dimethylaminoethyl-phenothiazine and 6 g. ofN-diethylaminoethyl-phenothiazine are 2 g. of 1:5-dibromo-pentane, thereis obtained heated for 30 hours on a boiling water bath with thedibromide of the above formula which melts 2.3 g. of1:5-dibromo-pentane. The gummy mass at 194-195 C. (Maquenne block,instantaneous). is dissolved in ethyl acetate and the moisture isextracted" The product which hals the above formula, is-thenrecrystallised from a mixture of alcohol and ether. -Me1ting point 1:1400."

(Maguenne block, instantaneous).

' meat 'IX" Preparation of the compound of the formula:

Preparation of the compound of the -formulaz s (I I) Br By proceeding asin Example IX but using 5.7 g. ofN-(2-dimethylamino-l-methyl-ethyD-phenothiazine and 2.2 g. oflzfi-dibromohexane there is obtained the dibromide of the above formula.Melting point about 290 C. (Maquenne block, instantaneous) I claim: 1. Acompound of the general formula:

on an 101mm..- --n-i I- cmn,).

R: Bl RI RI wherein R1 and R2 are selected from the class consisting ofhydrogen atom and alkyl groups,

OQIL 11.11)

. I cm).N--n-N cn,

Rs Rt Rs RA 7 wherein R3 and R4 are alkyl groups, n is an integergreater and 1 and less than 6, A is a divalent saturated aliphatichydrocarbon radicle and x 5 is a halogen atom.

3. A compound of the formula:

one

flM quseaah sqk-n iaer 2 than-65 A is a divalent saturated aliphatichydrocarbon radicle and X is .a halogen atom.

4. A compound of the formula:

a chain of up to 7 carbon atoms.

wherein} R1 'andRz are's elected from the class NJIH-CHg-N-CHr-CHr-CHr-CIIa-CHr-CHa-N-CHFAH '1. e

Hl CH: CH: C OH;

consisting of the hydrogen atom and alkyl groups, R: and R4 are alkylgroups, n is an integer greater than 1 and less than 6, and A is adivalent saturated aliphatic hydrocarbon radicle, which comprisesreacting a dihalogenoalkane with a compound of the general formula:

and separating the said phenothiazine derivative from the reactionmixture.

6. A process for the preparation of a phenothiazine derivative of thegeneral formula:

and separating the said phenothiazine derivative wherein n is an integergreater than 1 and less 75 from the reaction mixture.

i-x is a halogen atom and A is a divalent saturated .aliphatichydrocarbon radical havi 5. A process for the preparation of a phenothiazine derivative of the general formula:

"I; A process for the preparation of .a ipheno thiazine derivative ofthe general formula:

halogeno aIkane with a compound of the general f ormula: V H

CH3 and separating the said phenothiazine derivative from the reactionmixture.

8. A process for the preparation of a pheno thiazine derivative of thegeneral formula 8*? where R: andm are ,alkyigroups and A is i divalentsaturated aliphatic hydrocarbon radicie containing up to 7 carbonatoms,which comprises reacting adihalogeno alkane containing up to '7 carbonatoms with a compound of the general formula:

V I v V r V i \N /Ra JHzCHzN R4 and separating the said phenothiazinederivative from the reaction mixture,

' PAUL CHARPENTIER.

REFERENCES CITED The following references are of record in the file ofthis patent: a

Hackh, Chemical Dictionary (3rd edition) Pp. 32-3 3 (1944).

Patent No. 2,480,355"

Certificate of Correction 1 August 30, 1949 PAUL OHARPENTIER It ishereby certified the-terror appears in the printed specification of theabove numbered patent requiring correction as follows:

Column 5, line 64, for the words greater and read greater than; and thattherseid Letters Patent should be read with this correction therein thatthe same may conform to the record-of the c fiq l the Patent Ofiice.

Signed andsealed this 3rd= day of Jeniierj Ar: B11950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents.

